A critical early step of infection of virus in vivo strongly depends on successful infection to generate progeny virus at the primary infection site. If the host can trigger a mechanism to modulate viral replication in the primary infection site, the chance for virus to develop successful infection will be diminished. Class I MHC molecules have been known as antigen presenting molecules to T cell. There is, however, substantial evidence that class I MHC may play other roles which are less clearly defined for biology of cellular metabolism. The phenomena of association of class I MHC molecules with several cellular receptors at the cell surface have been suggested. Furthermore there have been several reports that H-2 loci of mouse is involved in the susceptibility of several viruses. The significance of these phenomena is largely unknown. With the recent development of the understanding of the structure of class I MHC molecules and their implication to its function, the role of MHC molecules on phenomena other than antigen presentation function can now be evaluated. In this proposal we want to examine the molecular basis of the host defense against viral infection and the mechanism of virus escape from host defense. We are using Sindbis virus (SIN) as a model system to study the interaction between virus and host cells. During the studies of the last several years, we have obtained provocative unexpected evidence that specific class I MHC molecules can act directly to inhibit the replication of the Sindbis virus in culture. The evidence to data suggests that the resistance mechanism can be directly mapped to specific class I MHC molecules and that there are allelic specific difference for their resistance. These results strongly suggest that class I MHC molecules may play an important role for the host defense mechanism, beyond their antigen presenting function. We wish to examine the nature of interaction between SIN and class I MHC molecules which lead to the class I MHC linked suppression of the virus replication. For this work, we will use virus strains which exhibit either resistance or susceptible to the class I MHC mediated inhibition in cell culture. We will examine the molecular basis of the resistance or susceptibility to productive infection. And at the stand point of class I MHC molecule, the potential mechanism by which specific class I MHC molecule mediated inhibition of virus replication will be examined. We will also examine the in vivo significance of this phenomena utilizing B10 congenic mice which differ only in H-2 loci and gene knock out mice.